The goal of this project is to provide detailed atomic-level understanding of the structural determinants that affect selective and potent inhibition of the activity of cysteine protease involved in parasitic infection. The causative agents of Chagas' disease, African sleeping sickness, malaria and leishmaniasis (Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum and several Leishmania species, respectively) each contain cysteine proteases that are critical to the life cycles or the organisms. These proteases have been identified and biochemically characterized. In collaboration with William Roush's synthetic chemistry group, the chemical, electrostatic and steric topology of these cysteine proteases will be mapped via high resolution X-ray crystallographic structures of the enzymes bound to several series of small molecule synthetic inhibitor. Macromolecular endogenous inhibitors of the proteases will also be studied in complex with the enzymes in order to detail extended modes of recognition and the impact of allosteric effects. As structural information has been the basis for numerous advances in the development of new therapeutics in the last 25 years, insights obtained from both small and macromolecular complex structures will be used as starting points for next cycles of rational design of inhibitors. This work will be done in collaboration with the Roush group as well as the Fred Cohen/Andrej Sali computational cores.